IP Library › Granted Patent US 10,570,090

Granted Patent B2

US 10,570,090 · App. 15/613,689 · Granted Feb 25, 2020

Substituted 6,7-dihydro-5H-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof

Inventors: Monsif Bouaboula (Paris, FR); Maurice Brollo (Paris, FR); Victor Certal (Paris, FR); Youssef El-Ahmad (Paris, FR); Bruno Filoche-Romme (Paris, FR); Frank Halley (Paris, FR); Gary McCort (Paris, FR); Laurent Schio (Paris, FR); Michel Tabart (Paris, FR); Corinne Terrier (Paris, FR); Fabienne Thompson (Paris, FR)

Assignee: SANOFI

C07D207/12 C07D401/12 C07D403/12 C07D405/12 C07D413/12 C07D417/12 C07D471/04 C07F5/025 C07F7/0812

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Quick Facts

Patent No.: US 10,570,090
App. No.: 15/613,689
Granted: Feb 25, 2020
Kind: B2

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Abstract

Compounds of formula (I): wherein R1 and R2 represent hydrogen or deuterium atoms; R3 represents a hydrogen atom or a —COOH, a —OH or a —OPO(OH) 2 group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a —OH group; wherein at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a —COOH, —OH or —OPO(OH) 2 group, then R5 represents a hydrogen atom; when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms; and R6 is selected from an optionally substituted phenyl, heteroaryl, cycloalkyl and heterocycloalkyl group; and the preparation and the therapeutic uses of the compounds of formula (I) as inhibitors and degraders of estrogen receptors, useful especially in the treatment of cancer.

Claims (69)

1. A method of treating a disease involving inhibition and degradation of estrogen receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

wherein:

R1 and R2 represent independently a hydrogen atom or a deuterium atom;

R3 represents a hydrogen atom, a —COOH group, a —OH group, or a —OPO(OH) 2 group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a hydrogen atom or a —OH group;

wherein:

at least one of R3 or R5 is different from a hydrogen atom;

when R3 represents a —COOH group, a —OH group or a —OPO(OH) 2 group, then R5 represents a hydrogen atom; and

when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms;

R6 is selected from the group consisting of

a phenyl group or a heteroaryl group comprising 3 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur, said phenyl and heteroaryl groups being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a (C 1 -C 6 )-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a —OH group; a (C 1 -C 6 )-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C 1 -C 6 )-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C 1 -C 6 )-alkyl group wherein said (C 1 -C 6 )-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C 1 -C 6 )-alkyl groups; an amine group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; an amide group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; and

a cycloalkyl group or a heterocycloalkyl group comprising 4 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur, said cycloalkyl or heterocycloalkyl groups being saturated or partially saturated and being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a fluorine atom; a —OH group; a (C 1 -C 6 )-alkyl group; a —COOR7 group wherein R7 is an (C 1 -C 6 )-alkyl group; and an oxo group;

or a pharmaceutically acceptable salt thereof;

wherein said disease is selected from the group consisting of ovulatory dysfunction, endometriosis, osteoporosis, benign prostatic hypertrophy, inflammation, and an estrogen receptor dependent cancer selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, uterine cancer, cervical cancer, and metastasis of said estrogen receptor dependent cancer.

2. A method of treating ovulatory dysfunction, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of

formula (I):

wherein:

R1 and R2 represent independently a hydrogen atom or a deuterium atom;

R3 represents a hydrogen atom, a —COOH group, a —OH group, or a —OPO(OH) 2 group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a hydrogen atom or a —OH group;

wherein:

at least one of R3 or R5 is different from a hydrogen atom;

when R3 represents a —COOH group, a —OH group or a —OPO(OH) 2 group, then R5 represents a hydrogen atom; and

when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms;

R6 is selected from the group consisting of

3. A method of treating an estrogen receptor dependent cancer selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, uterine cancer, cervical cancer, and metastasis of said estrogen receptor dependent cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

wherein:

R1 and R2 represent independently a hydrogen atom or a deuterium atom;

R3 represents a hydrogen atom, a —COOH group, a —OH group, or a —OPO(OH) 2 group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a hydrogen atom or a —OH group;

wherein:

at least one of R3 or R5 is different from a hydrogen atom;

when R3 represents a —COOH group, a —OH group or a —OPO(OH) 2 group, then R5 represents a hydrogen atom; and

when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms;

R6 is selected from the group consisting of

4. The method according to claim 3 , wherein the metastasis is a cerebral metastasis.

5. The method according to claim 3 , wherein the estrogen receptor dependent cancer is resistant to anti-hormonal treatment.

6. The method according to claim 2 , wherein for the compound of formula (I), R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a (C 1 -C 6 )-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a —OH group; a (C 1 -C 6 )-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C 1 -C 6 )-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C 1 -C 6 )-alkyl group wherein said (C 1 -C 6 )-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C 1 -C 6 )-alkyl groups; an amine group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; an amide group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group;